This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In ALS, the prominent clinical feature is weakness presumed to be secondary to degeneration of motor neurons. However, the death of these cells occurs late in the disease process and there are large numbers of surviving motor neuron cell bodies in human postmortem material that should be able to support considerable strength. Denervation of muscles or malfunction of the neuromuscular junction appears to occur prior to the onset of overt clinical symptoms and indeed is most likely the cause of muscle weakness in ALS as opposed to motor neuron death in the spinal cord. These results have prompted the hypothesis that weakness in ALS may be initiated by a dying back motor axon neuropathy which, in turn, may cause disruption in the cell bodies.